Vaccines and antibiotics permitted to combat many infectious diseases. While a wealth of vaccines has been developed, natural evolution and engineering for bioterrorism purposes creates a novel biothreat for which novel vaccines are needed. Dendritic cells (DCs) play a central role in the differentiation of immune effectors and thus are a major target for vaccination. Given the fact that distinct human DC subsets differentially control lymphocytes, it is important to understand how distinct DC subsets modulate vaccine immunity in vivo. Such knowledge will permit us to design targeted vaccines that will induce a desired type of immunity. Vaccines need to be tested in vivo but studies in mice often cannot be directly extrapolated to humans because of biological differences. Hence, the need for pre-clinical models of the human immune system for testing vaccine efficacy. With this in mind, The goal of the Center is to develop effective diagnostic, prognostic, and therapeutic measures against NIAID Category A-C pathogens through a focus on human dendritic cell subsets, which act as innate effectors as well as initiators and coordinators of adaptive immune responses. Objectives: 1. Develop our in vivo model of human immune responses based on mice reconstituted with a full human immune system. 2. Generate novel monoclonal antibodies identifying i) the various human DC subsets at their various stages of maturation, and ii) peptides derived from biothreat antigens presented by dendritic cells 3. Determine how Category A-C pathogens alter human dendritic cells in vitro and in vivo. 4. Determine the effects of Category A-C pathogens on the human immune system in vivo. 5. Identify the in vivo biosignatures of human Category A-C pathogens to allow rapid biothreat diagnosis, prediction of disease severity and initiation of biothreat specific treatment. 6. Test and identify in vivo novel human vaccines as biothreat countermeasures. The Program will include a Technical Development Component, four projects, 3 Core facilities: Administration, Microarray and Luminex multiplex analysis, and Education component. Two pilot projects are also proposed. Center will be based at the Baylor Institute for Immunology Research at Dallas and will include Investigators at Yale U., Rockefeller U., NIAID, U. of New Mexico and UT Southwestern. By harnessing human DC subsets in vivo we surmise that we will able to propose novel potent vaccines to protect humans against category A-C pathogens.